After a bit of ranting earlier this week, I thought now would be a good time to cool it down a bit, if only for a moment. There’s plenty more out there to rant about, but I’m intentionally ignoring it, if only for a day (or even half a day). If there’s one thing I’ve learned about blogging in the three years I’ve indulged in this little habit of mine, it’s that a blogger has to mix things up. Too many rants in a row, and even I start to get bored. And if I’m bored you’re almost certainly bored.

We wouldn’t want that, now, would we?

So it was with great interest that I came across, albeit somewhat belatedly, this story about a recent study. If there’s one claim that supporters of so-called “alternative” medicine like to make, it’s that supplements or vitamins can prevent cancer. Particularly favored are vitamins C, D, and E as anti-cancer talismans. In the more extreme form, this claim even sometimes goes so far as claiming that one or more of these, along with other supplements, can actually treat cancer. Of course, the situation is far more complicated, as I discussed a while back about a claim that vitamin D is an all purpose cancer preventative. Vitamin D may prevent some cancers, but it may also accelerate others. Whether vitamin D supplementation is on balance more beneficial than harmful is thus not nearly as clear-cut as certain cranks would make it sound.

Well, wouldn’t you know it, but another group recently looked at the relationship between vitamins C and E and cancer. Once again, the results were disappointing. Moreover, one of the findings suggests that vitamin supplementation may slightly increase the risk of cancer.
The study was published a week ago in the American Journal of Respiratory and Critical Care Medicine by a group led by Dr. Christopher Slatore at the University of Washington collaborating with a group from the University of North Carolina Chapel Hill and entitled Long-Term Use of Supplemental Multivitamins, Vitamin C, Vitamin E, and Folate Does Not Reduce the Risk of Lung Cancer.1 It’s title more or less describes its conclusions.

The study examined the role of supplementation in the prevention of lung cancer. At the very beginning, the authors describe well the rationale that makes supplementation as a cancer preventative measure so attractive:

Fruits and vegetables are associated with a lower incidence of lung cancer (7), but because dietary habits are difficult to change (8), there is considerable interest in supplemental vitamins for chemoprevention. Supplements are used by over half of adults in the United States (9), and a majority of them believe they are “good for health and well-being” (10). This belief that supplements are helpful, or at least safe, is controversial because there is growing evidence to the contrary and some supplements are associated with an increased risk of death (11, 12). A systematic review of randomized controlled trials found little evidence that vitamin supplementation prevents chronic disease, including cancer (13), and a National Institutes of Health (NIH) panel did not make recommendations about their use (14), noting the lack of research with “accurate and current data on the public’s total intake of these nutrients.”

Yes, it’s much more seductively easy to take a pill rather than to make the effort to eat a healthier, more balanced diet. Indeed, that’s one of the things I always wondered about when it comes to “complementary and alternative” medicine (CAM) claims. After all, if there is one aspect of “CAM” claims, it’s that natural is better, coupled with an inherent distrust of pharmaceuticals and taking pills. Yet, what do many “CAM” mavens recommend to prevent or treat disease? Taking supplements in the form of pills. But I digress.

In any case, the authors examined data from a large cohort known as VITAL (VITamins And Lifestyle). This particular cohort was part of a study designed specifically to examine the association between supplement use and cancer in the general population, and in particular lung cancer. Of course, lung cancer is primarily associated with cigarette smoking, and indeed it’s estimated that over 90% of lung cancers are directly attributable to tobacco use. In any case, the VITAL cohort consists of 77,719 people aged 50-76 in the Puget Sound area who filled out detailed questionnaires about their health, cancer risk factors, and supplement use between 2000-2002, of whom 70% provided DNA specimens by buccal swab. One of the biggest problems with following a cohort this large is, well, following the cohort. The useful thing about the VITAL database is that it has a passive followup system that links patients to the SEER database annually, identifying patients diagnosed with cancer. Even better, it tracks participants who move out of the Puget Sound area through the National Change of Address file annually by using a vendor who contracts with the US Postal Service. The system identifies correctly at least 65% of moves, and “possible” moves are followed up manually with letters and attempts to contact the person. It’s also useful in that it has a far more detailed assessment of supplement use over at least the ten years prior to the filling out of the questionnaire than most studies, and rigorous quality control measures were implemented.

Using this database, Slatore and colleagues examined the association between the use of vitamin C and vitamin E and the later incidence of lung cancer. First, they noted that 521 subjects developed lung cancer in the years following 2002. After controlling for confounding factors, they found that prior history of cancer, COPD, a family history of lung cancer, and BMI were associated with lung cancer were all associated with an increased risk of cancer, along with, unsurprisingly, cigarette smoking. There was, however, no association between lung cancer and the use of vitamin C or folate supplementation that could be detected. Specifically, the ten year average intake of these supplements, whether continuous or intermittent, was not associated with a change in lung cancer risk. Neither was lung cancer type or morphology (small cell versus non-small cell, for instance) associated positively or negatively with these two supplements. In contrast, there was association between vitamin E use and lung cancer. Specifically, there was a small increase in the risk of lung cancer among long term users of vitamin E, on the order of a relative risk of 1.05 for every 100 mg per day increase in dose. This effect was largely confined to current smokers and greater for non-small cell lung cancer (in essence, adenocarcinomas and squamous cell carcinomas).

Of course, this study was an epidemiological study. Although it was prospective, it is prone to all the potential confounding factors and biases to which all epidemiological studies can fall prey. This study, however, had a number of strengths that help it avoid many of these problems, including a rigorous assessment of supplement dose over a long period of time that has been validated, care in accounting for confounding factors, and the automatic linkage to the SEER database. On the other hand, despite the large size of this cohort, the study’s power is limited to reliably detecting only a 30% or greater increase or decrease in incidence, and the study enrollees consist of a higher proportion of nonsmokers than the general population. Smaller effects may not have been detected. Be that as it may, this study is important because it is the largest prospective study of its kind thus far. At the very least it is fairly strong evidence that supplementation with vitamin C, vitamin E, or folate does not decrease the risk of lung cancer. At the most, it suggests that current smokers should not be taking vitamin E supplementation, as, if this study is correct, it will increase the already high risk of lung cancer. Once again, this study is more evidence suggesting that at higher doses vitamin E might go from being an antioxidant to a pro-oxidant, which is what might account for this result.

We all want a “magic bullet” to make us healthy. I’m no different; indeed, like many physicians, I’m fairly weak when it comes to diet. I love fast food as much as the next guy, and if my wife doesn’t prod me I tend to be too lazy to eat a healthy diet, particularly when work gets really busy (and, sad to say, when it might take time away from other activities, such as blogging). I’d love it as much as the most die-hard supplement maven if taking a few pills could counteract all my bad lifestyle choices. Unfortunately, biology and human physiology don’t always cooperate with our wishful thinking, and this study is just one more bit of evidence that this is true.

There is a clear and simple explanation for the observations that supplemental vitamins and antioxidants worsen health and that people who eat a self-selected diet rich in vitamins and antioxidants have better health.

Diet choice is part of the control system that physiology uses to regulate the level of oxidative stress. If you have a high oxidative stress setpoint, you self-select a diet devoid of antioxidants so that your body doesn’t need to destroy them metabolically. Antioxidants are easy to destroy, the body simply makes more superoxide (which it can do in unlimited quantities). Eating more antioxidants than your physiological oxidative stress setpoint requires increases the level of superoxide your body must make to destroy the excess.

This simple explanation explains both the observation of no benefits from supplemental antioxidants (and perhaps some harm), and also the observation that a self-selected diet rich in antioxidants is associated with good health. Choosing a healthy diet is an effect of good health, not the cause.

This is why dietary change is so difficult. There are many physiological processes regulating dietary choice and they cannot easily be over ridden.

As a cancer survivor, I find myself drawn more and more to a diet heavy on the raw,leafy and colorful end of the food spectrum. I’ve always eaten pretty well, but my body wants this kind of food more these days. Processed, preservative laden stuff seems to burn my mouth. Is this a result of chemo, or just my body trying to hedge its’ bet? I guess only time will tell, but popping a vitamin pill instead of eating healthy doesn’t cut it for me.

daedalus, that explanation makes a little sense to me but it seems would only be effective with people who know how to listen, I mean REALLY listen, to their bodies. And it doesn’t take addiction into account. Do all of us sugar addicts crave sugar because our bodies want it? Of course not; sugar’s an addictive substance.

Emotional eating is also at work. I still want those Oreos and milk after school over forty years later, even though intellectually I know Oreos and milk are bad for me and I’ll just put on weight if I eat them.

I still do the one a day multivitamin thing because I know my diet’s terrible. I’ve not come down with scurvy or rickets yet, so I guess they work that well at least.

You really do have to make a lifestyle change in order to eat right consistently. I’ve thought about going the NutriSystem route, but hate the idea of depending on a company to hold my hand on such a thing, and I figure I won’t actually learn any good habits from it.

DonZilla, That is exactly what addictions are, they are your body shouting at you to do xyz, even if it is detrimental. Oxidative stress is a control parameter. It changes physiology a lot, so it is used a lot. Your body is telling you to do it because it wants/needs to invoke a state of oxidative stress.

There is a very big problem of bias in diet trials. Pretty much all of the diet trials are retrospective, and the participants are segregated by those who choose to eat green leafy vegetables and those who choose to eat something else.

Pretty much every long term prospective trial of supplemental antioxidants has shown no or a slightly negative effect. If supplemental antioxidants don’t control oxidative stress, then oxidative stress is not controlled at all by diet and how what levels of what antioxidants are consumed.

Vitamins from supplements and vitamins from vegetables are the same exact molecules. There is no plausible physiological mechanism by which the same molecules from different sources could have different physiological effects.

The hypothesis that diet selection is part of the body’s oxidative stress control system is consistent with both the retrospective diet data and the prospective supplement data. It does explain the association of diet with illness. Diet choice is caused by the state of oxidative stress of the body, not the other way around.

As far as I can tell this hypothesis is consistent with all the studies. Prospective studies of supplemental antioxidants as well as retrospective studies of diet provided the studies are large, well done and long. Short studies may show acute effects, but according to this hypothesis physiology adjusts and the effects go away over time. The meta study linked to above in the JAMA shows this quite robustly.

I discuss some similar aspects of this in my blog on the myth of homeostasis. I call it a myth because it is completely incorrect. Nothing in physiology is static. There is no mythic principle of homeostasis keeping things static. Everything is dynamic. The only time any part of an organism’s physiology is static is when the organism is dead.

Mostly I discuss this in terms of blood glucose regulation. I see the metabolic syndrome not as “dysregulation”, (i.e. bad regulation around a good setpoint), I see it rather as good regulation around a bad setpoint.

Physiology didn’t evolve to keep things static, it evolved to keep things alive. There is no evolutionary driving force for stasis. If organisms can better survive by changing parameters, any and all parameters are “fair game”, and organisms will evolve to change them if it aids survival or reproduction.

I see the metabolic syndrome as a completely adaptive response to not enough mitochondria.

I still cannot believe that so many people do things because they sound like a good idea, while there is no evidence that they help. The entire supplement industry is an excellent example, but only one of many.

Besides, there if there are no “side-effects” there are likely no “effects”.

Oh yeah (I like to rant too, I don’t get bored with it), I still can’t believe that after a number of examples where supplements have caused harm the FDA hasn’t required trails showing at least that there is no negative effect from supplements. Wishful thinking I guess.